Pharmacokinetics of prolonged-release tacrolimus versus immediate-release tacrolimus in de novo liver transplantation: A randomized phase III substudy

Background With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses. Methods This sub-study of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1mg/kg/day) during the first 2 weeks post-transplant. Results Pharmacokinetic data were analysed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC0–24) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC0–24 (normalized to 0.1mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC0–24 and concentration at 24 hours after the morning dose (r=0.96 and r=0.86, respectively), and the slope of the line of best fit was similar for both formulations. Conclusions Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials . gov number: NCT00189826) Discipline liver transplantation/hepatology, immunosuppression/immune modulation. This article is protected by copyright. All rights reserved.